2-203726685-G-A

Variant names:

• chr2-203726685-G-A
• rs41272649
• NM_006139.4:c.105G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006139.4(CD28):​c.105G>A​(p.Ala35Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,932 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (131 hom.)
• Consequence: CD28 NM_006139.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.24
• Publications: 8 publications found

Genes affected

CD28 (HGNC:1653): (CD28 molecule) The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

CD28 Gene-Disease associations (from GenCC):

• immunodeficiency 123 with HPV-related verrucosis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-203726685-G-A is Benign according to our data. Variant chr2-203726685-G-A is described in ClinVar as Benign. ClinVar VariationId is 774413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD28	NM_006139.4	c.105G>A	p.Ala35Ala	synonymous_variant	Exon 2 of 4	ENST00000324106.9	NP_006130.1
CD28	NM_001410981.1	c.147G>A	p.Ala49Ala	synonymous_variant	Exon 2 of 4		NP_001397910.1
CD28	NM_001243077.2	c.105G>A	p.Ala35Ala	synonymous_variant	Exon 2 of 4		NP_001230006.1
CD28	NM_001243078.2	c.53-2963G>A		intron_variant	Intron 1 of 2		NP_001230007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD28	ENST00000324106.9	c.105G>A	p.Ala35Ala	synonymous_variant	Exon 2 of 4	1	NM_006139.4	ENSP00000324890.7
CD28	ENST00000458610.6	c.147G>A	p.Ala49Ala	synonymous_variant	Exon 2 of 4	1		ENSP00000393648.2
CD28	ENST00000374481.8	c.53-2963G>A		intron_variant	Intron 1 of 2	1		ENSP00000363605.4
CD28	ENST00000718458.1	c.95-2963G>A		intron_variant	Intron 1 of 2			ENSP00000520836.1

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1124 AN: 151984 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00908

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00712 AC: 1791 AN: 251418 AF XY: 0.00701

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.0117 AC: 17136 AN: 1461830 Hom.: 131 Cov.: 32 AF XY: 0.0112 AC XY: 8175 AN XY: 727222

African (AFR) AF: 0.00167 AC: 56 AN: 33478

American (AMR) AF: 0.00389 AC: 174 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86256

European-Finnish (FIN) AF: 0.0102 AC: 545 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0139 AC: 15493 AN: 1111972

Other (OTH) AF: 0.0126 AC: 759 AN: 60396

GnomAD4 genome AF: 0.00739 AC: 1124 AN: 152102 Hom.: 4 Cov.: 32 AF XY: 0.00751 AC XY: 558 AN XY: 74346

African (AFR) AF: 0.00239 AC: 99 AN: 41486

American (AMR) AF: 0.00602 AC: 92 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4802

European-Finnish (FIN) AF: 0.00908 AC: 96 AN: 10574

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 812 AN: 67994

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00970 Hom.: 12

Bravo AF: 0.00722

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.00960

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CD28: BP4, BP7, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.38
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41272649; hg19: chr2-204591408;